Beneath the fanfare of RemberTM—the first tau-based Alzheimer disease treatment with publicly reported Phase 2 trial results (see ARF ICAD story)—the International Conference on Alzheimer’s Disease, held last month in Chicago, featured some noteworthy preclinical and basic science tau developments. This story highlights a few of them, but all readers are cordially invited to use the comment box below to add their own notes and observations about other tau-related highlights at ICAD. Einar Sigurdsson of New York University School of Medicine presented data that may strengthen the case for tau-based immunotherapy: in his new AD mouse model, a phospho-tau immunogen not only cleared tau pathology, but also seemed to prevent cognitive decline. Cathy Andorfer of Mayo Clinic in Jacksonville, Florida, also reported on prevention of cognitive decline, neurodegeneration, and tau pathology in an aggressive tauopathy mouse model—but her team used a brain-penetrant microtubule stabilizer under development as a cancer drug at Bristol-Myers Squibb, Wallingford, Connecticut. Meanwhile, molecular insight into a possible role for tau’s non-microtubule binding domain in Aβ-mediated neurodegeneration came from a presentation by Jürgen Götz of the University of Sydney, Australia. (For Andorfer and Götz, see Part 2 and Part 3.)

Preventive Tau Vaccine Improves Cognition in Tauopathy Mice
In an earlier study demonstrating the feasibility of a phospho-tau vaccine approach, Sigurdsson and colleagues immunized transgenic mice expressing the human tau mutant P301L, which develop rapid and aggressive tau pathology. With immunizations starting at two months of age, the tau peptide (a 30-amino-acid fragment phosphorylated at two sites) triggered a specific antibody response that cleared tau aggregates and improved motor performance when assessed at five and eight months (see ARF related news story). However, the real proof of principle is whether the tau-based immunotherapy could prevent cognitive decline. For this, the P301L mice are ill-suited, Sigurdsson said, as older animals develop motor impairments that would interfere with common tests of rodent cognition such as those that involve maze running.

To skirt this problem, the researchers set out to test their immunization protocol in hTau mice, which express all six wild-type isoforms of human tau on a mouse tau knockout background (Andorfer et al., 2003). These mice better resemble AD in that they develop tau pathology primarily in the cortex and hippocampus with very little in areas important for motor activity (e.g., brain stem, spinal cord). For the immunization studies, hTau mice would pose other challenges, though. The onset of disease varies considerably in them, such that some animals show extensive pathology by nine months, while others may not until 15-18 months. This slow development of pathology would also drag out the evaluation of immunotherapy.

While gearing up for the hTau studies, Allal Boutajangout of Sigurdsson’s group was trying to address a separate issue—the effect of mutant presenilin-1 (PS1) on tau pathology—by crossing the hTau mice with a transgenic line expressing mutant PS1 (M146L). These double transgenics were breeding faster than the hTau mice, Sigurdsson said, so Boutajangout and colleagues ended up testing their phospho-tau immunogen in the hTau/PS1 mice, using the hTau animals as internal controls. (They decided this before learning that mutant PS1 accelerates tau pathology, serendipitously enabling quicker completion of the immunotherapy studies.)

As with the studies in P301L mice, Sigurdsson’s team began immunizing at two to three months, boosted two weeks later, and continued with monthly injections. Starting at seven to eight months, the mice faced three cognitive tests and were sacrificed at eight to nine months. The phospho-tau peptide stimulated an IgM/IgG response and reduced tau aggregates by 56 percent in the pyriform cortex in immunized mice, Sigurdsson reported. Importantly, the reduction of tau aggregates correlated with cognitive improvements assessed by three tests—radial arm maze, closed field symmetrical maze, and object recognition test. The cognitive differences did not stem from movement defects, as all groups did equally well on motor tests. The researchers have not yet looked at markers of inflammation¬—a potential side effect that has plagued human immunotherapy trials—but would like to in the future, Sigurdsson told this reporter.

Because hTau/PS1 mice typically develop their first hints of tau pathology around two to three months of age, the vaccine in those studies essentially functioned as a prophylactic. Sigurdsson said his group has begun testing their immunotherapy protocol in older animals—starting injections at eight months to see if the treatment can reverse tau pathology and cognitive deficits. They are also looking to immunize with different tau epitopes, and are doing studies to further tease out the mechanisms, e.g., how do the anti-tau antibodies reach and bind to brain neurons, and clear tau aggregates? For a different approach to treating tauopathy mice, see Part 2 of this series.—Esther Landhuis.

This is Part 1 of a three-part series on tau. See also Part 2 and Part 3.

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References

News Citations

  1. Chicago: Out of the Blue—A Tau-based Treatment for AD?
  2. Chicago: Brain-Penetrant Microtubule Stabilizer in Tauopathy Mice
  3. Chicago: Tau Projection Domain May Block Excitotoxicity in Mice
  4. Tau Vaccine Detangles Mouse Brain

Paper Citations

  1. . Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J Neurochem. 2003 Aug;86(3):582-90. PubMed.

Other Citations

  1. human tau mutant P301L

External Citations

  1. hTau

Further Reading

News

  1. Tau Vaccine Detangles Mouse Brain
  2. Chicago: Studies Probe Diminishing Placebo Decline, Part 1
  3. Chicago: Studies Probe Diminishing Placebo Decline, Part 2
  4. Chicago: Trial Design Bedevils Search for New AD Drugs, Part 1
  5. Chicago: The Phase 2 Problem and the Way to a Surrogate, Part 2
  6. Chicago: Out of the Blue—A Tau-based Treatment for AD?
  7. Chicago: Dimebon Safe for 18 Months
  8. Chicago: Bapineuzumab’s Phase 2—Was the Data Better Than the Spin?
  9. Chicago: ICAD Offered Mix Bag of Setbacks and Hopeful News
  10. Chicago: Lilly’s Antibody Appears to Do No Harm, But Will It Help?
  11. Chicago: APP Roles in Caspase Gene Regulation, Muscle Function?
  12. Chicago: Flurizan Postmortem